chr1-33013242-A-T

Position:

• chr1-33013242-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001625.4(AK2):​c.659T>A​(p.Phe220Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F220F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AK2 NM_001625.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.13

Genes affected

AK2 (HGNC:362): (adenylate kinase 2) Adenylate kinases are involved in regulating the adenine nucleotide composition within a cell by catalyzing the reversible transfer of phosphate groups among adenine nucleotides. Three isozymes of adenylate kinase, namely 1, 2, and 3, have been identified in vertebrates; this gene encodes isozyme 2. Expression of these isozymes is tissue-specific and developmentally regulated. Isozyme 2 is localized in the mitochondrial intermembrane space and may play a role in apoptosis. Mutations in this gene are the cause of reticular dysgenesis. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 1 and 2.[provided by RefSeq, Nov 2010]

ENSG00000236065 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.330618).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AK2	NM_001625.4	c.659T>A	p.Phe220Tyr	missense_variant	6/6	ENST00000672715.1	NP_001616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AK2	ENST00000672715.1	c.659T>A	p.Phe220Tyr	missense_variant	6/6		NM_001625.4	ENSP00000499935.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2024

The c.659T>A (p.F220Y) alteration is located in exon 6 (coding exon 6) of the AK2 gene. This alteration results from a T to A substitution at nucleotide position 659, causing the phenylalanine (F) at amino acid position 220 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.028	.;T;T;T
Eigen	Benign	-0.026
Eigen_PC	Benign	0.070
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.1	M;.;.;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Uncertain	0.42
Sift	Benign	0.12	T;T;T;T
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.13	B;P;.;B
Vest4		0.40
MutPred		0.50		Gain of phosphorylation at F220 (P = 0.0219);.;Gain of phosphorylation at F220 (P = 0.0219);Gain of phosphorylation at F220 (P = 0.0219);
MVP		0.46
MPC		0.22
ClinPred		0.70	D
GERP RS		4.0
Varity_R		0.28
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-33478843;